Targeting delivery of lipocalin 2-engineered mesenchymal stem cells to colon cancer in order to inhibit liver metastasis in nude mice
One of the major obstacles in cancer therapy is the lack of anticancer agent specificity to tumor tissues. The strategy of cell-based therapy is a promising therapeutic option for cancer treatment. The specific tumor-oriented migration of mesenchymal stem cells (MSCs) makes them a useful vehicle to deliver anticancer agents. In this study, we genetically manipulated bone marrow-derived mesenchymal stem cells with their lipocalin 2 (Lcn2) in order to inhibit liver metastasis of colon cancer in nude mice. Lcn2 was successfully overexpressed in transfected MSCs. The PCR results of SRY gene confirmed the presence of MSCs in cancer liver tissue. This study showed that Lcn2-engineered MSCs (MSC-Lcn2) not only inhibited liver metastasis of colon cancer but also downregulated the expression of vascular endothelial growth factor (VEGF) in the liver. Overall, MSCs by innate tropism toward cancer cells can deliver the therapeutic agent, Lcn2, and inhibit cancer metastasis. Hence, it could be a new modality for efficient targeted delivery of anticancer agent to liver metastasis.
KeywordsMesenchymal stem cells Lipocalin 2 Liver metastasis Nude mice Colon cancer
This research was supported by the grant awarded from the Iranian Council of Stem Cell Technology.
Conflicts of interest
All procedures performed in this study involving human participants were in accordance with the Ethical Standards of the Ethics Committee of Iranian Blood Transfusion Organization (ECIBTO) as well as the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Bone marrow samples were obtained from healthy donors with informed consent.
In addition, all procedures performed in this study involving animals were in accordance with the ethical standards of institutional guidelines and approved protocols.
- 2.Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN. Cancer incidence and mortality worldwide: IARC CancerBase No. 11. 2012.Google Scholar
- 9.Compte M, Cuesta AM, Sanchez-Martin D, Alonso-Camino V, Vicario JL, Sanz L, et al. Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds. Stem Cells. 2009;27(3):753–60. doi: 10.1634/stemcells. 2008-0831.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Choi SA, Lee JY, Wang KC, Phi JH, Song SH, Song J, et al. Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas. Eur J Cancer. 2012;48(1):129–37. doi: 10.1016/j.ejca.2011.04.033.CrossRefPubMedGoogle Scholar
- 18.Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, et al. Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy. 2010;12(5):615–25. doi: 10.3109/14653241003631815.CrossRefPubMedGoogle Scholar
- 21.Lim R, Ahmed N, Borregaard N, Riley C, Wafai R, Thompson EW, et al. Neutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor-induced epithelio-mesenchymal transition. Int J Cancer J Int du cancer. 2007;120(11):2426–34. doi: 10.1002/ijc.22352.CrossRefGoogle Scholar
- 22.Tong Z, Kunnumakkara AB, Wang H, Matsuo Y, Diagaradjane P, Harikumar KB, et al. Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Res. 2008;68(15):6100–8. doi: 10.1158/0008-5472.CAN-08-0540.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Halabian R, Tehrani HA, Jahanian-Najafabadi A, Habibi RM. Lipocalin-2-mediated upregulation of various antioxidants and growth factors protects bone marrow-derived mesenchymal stem cells against unfavorable microenvironments. Cell Stress Chaperones. 2013;18(6):785–800. doi: 10.1007/s12192-013-0430-2.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Mohammadzadeh M, Halabian R, Gharehbaghian A, Amirizadeh N, Jahanian-Najafabadi A, Roushandeh AM, et al. Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity. Cell Stress Chaperones. 2012;17(5):553–65. doi: 10.1007/s12192-012-0331-9.CrossRefPubMedPubMedCentralGoogle Scholar